ArticleAnnals of neurology2021
A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α-Synuclein Mice.
Article in Annals of neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 65 citations in OpenAlex.
- Quantifying the Acute Toxicity of Alpha-Synuclein Membrane-Accumulation in a Cell-Based Assay.Journal of molecular neuroscience : MN · 2026Article
- Elevation of Stearoyl-Coenzyme A Desaturase and Monounsaturated Fatty Acids in Parkinson's Disease Serum.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- The Emerging Parkinson's Disease Oxylipin-Ome.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.npj metabolic health and disease · 2026Article
- Glycerol 3-phosphate acyltransferase exacerbates α-synuclein-induced toxicity by increasing lipid peroxidation.Nature communications · 2026Article
- Parkinson disease is a fatty acidopathy.Nature reviews. Neurology · 2025Review
- Dysregulation of Monounsaturated Fatty Acids is Related to α-Synuclein in Multiple System Atrophy.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Stearoyl-CoA desaturase inhibition normalizes brain lipid saturation, α-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice.JCI insight · 2025Article
- The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria-ER membranes.NPJ Parkinson's disease · 2025Article
- Acute lipid droplet accumulation induced by the inhibition of the phospholipase DDHD2 does not affect the level, solubility, or phosphoserine-129 status of α-synuclein.Metabolic brain disease · 2025Article
- Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders.Molecular neurodegeneration · 2024Review
- Interactions of alpha-synuclein with membranes in Parkinson's disease: Mechanisms and therapeutic strategies.Neurobiology of disease · 2024Review
- Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Review
- Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism.Neurobiology of disease · 2024Article
- Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients.EMBO molecular medicine · 2024Article
- Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies.Metabolites · 2024Review
- Peptide set test: a peptide-centric strategy to infer differentially expressed proteins.Bioinformatics (Oxford, England) · 2024Article
- Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer's disease mouse model.Scientific reports · 2024Article
- Review
- Generation of G51D and 3D mice reveals decreased α-synuclein tetramer-monomer ratios promote Parkinson's disease phenotypes.NPJ Parkinson's disease · 2024Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
objectiveParkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl-coenzyme A desaturase (SCD) inhibitor ("5b") that prevented αS-positive vesicular inclusions and cytotoxicity in cultured human neurons.
methodsOral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild-type human αS (WT) or an amplified familial PD αS mutation (E35K + E46K + E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD-like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD-related lipid changes were quantified in 5b- versus placebo-treated mice. Outcomes were compared to effects of crossing 3K to SCD1
results5b treatment reduced αS hyperphosphorylation in E46K-expressing human neurons, in 3K neural cultures, and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD-like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS tetramers and reduced proteinase K-resistant lipid-rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation.
interpretationProlonged reduction of brain SCD activity prevented PD-like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human α-synucleinopathies. ANN NEUROL 2021;89:74-90.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.